Field of the Invention
[0001] The present invention relates to a process for the preparation of the compounds of
Formula I which have been shown to have activity as HCV protease inhibitors. The present
invention relates also to a process for the preparation of intermediate compounds
useful in preparing the compounds of Formula
I.
Background
[0002] Identification of any publication in this section or any section of this application
is not an admission that such publication is prior art to the present invention.
[0003] A process for making the compound of Formula I
, (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]-amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
is described in
U.S. Patent no. 7,012,066 (the '066 patent), Example XXIV, beginning at Column 448 therein. Additional processes
for the preparation of the compounds of Formula I are described in published
U.S. patent application nos. 2005/0249702, published November 10, 2005, and
2005/0059800, published March 17, 2005.
[0004] In general, the process for the preparation of compounds of Formula I is illustrated
in Scheme I
:
[0005] In accordance with Scheme I, compounds of formula I have been prepared by coupling
the compound of Formula Ia with the compound of Formula Ib, preferably, as illustrated
in published
U.S. application no. 2005/0059800, by treating an acetonitrile solution of 2,6 lutidine and the compound of Formula
Ia with an acetonitrile solution containing the compound of Formula Ib, ethyl[(3-dimethylamino)propyl]carbodiimide
hydrochloride salt (EDCI-HCl), and 1-hydroxybenzotriazole hydrate (HOBt). After the
coupling reaction is complete the reaction mixture provided by Step 1 is worked up
by adding methyl-tertiarybutyl ether (MTBE), adjusting the pH with HCl, extracting
with sodium bicarbonate and concentrating the organic solution. The concentrate is
then diluted with acetonitrile and reconcentrated, then treated with aqueous lithium
hydroxide followed by an HCl/isopropyl acetate solution to liberate the free acid,
and finally treated with L-α-methylbenzylamine to precipitate the 1c salt form of
the coupled product, wherein "salt" is the counter ion of Formula
1f (L-α-methylbenzylamine).
[0006] As illustrated in Scheme I, the compound of Formula
I is provided from the compound of Formula
Ic using one of two processes. In one process, shown in Steps 2'a and 2'b, a three step
procedure, the free acid is generated from the compound of Formula
Ic (by treatment with acid, subsequently removing the L-α-methylbenxylamine counterion).
The free acid form of
Ic is coupled with amine
Id' followed by oxidation of the coupled product.
[0007] In an alternative process, shown in Scheme I as Step 2, the free acid form of compound
Ic is coupled with the amine
Id to provide the compound of Formula I directly. Accordingly, with reference to the
'066 patent, the coupling process of Step 2 can carried out by treating a DMF/CH
2Cl
2 solution of the free acid form of compound
Ic with amine
Id' in the presence of EDCI, HOBt, and N-methylmorpholine to provide the coupled product.
After the coupling reaction is complete, the reaction mixture is concentrated, treated
with aqueous HCl and the aqueous layer is extracted with dichloromethane. The dichloromethane
extract is washed in turn with aqueous NaHCO
3, aqueous HCl, and brine, dried with MgSO
4, and dried to a solid under vacuum. The alcohol functional group of the coupled product
is then oxidized to provide the compound of Formula I. Oxidation can be carried out
by treatment with EDCI in mixed toluene/DMSO in the presence of dichloroacetic acid.
[0008] In accordance with the foregoing, the previous processes for the preparation of the
compound of Formula I using Scheme I requires the use of 1-hydroxy benzotriazole in
the first amidation reaction coupling the compounds of formula Ia and Ib to form the
intermediate compound of formula Ic. Since HOBt is classified as a reactive solid,
and therefor storage and transport of the material is regulated, its use in commercial
scale manufacture entails difficuties in handling and storage, and therefore it is
desirable to minimize the number of steps in which it is employed. Moreover, when
generating the free acid form of the compound of Formula Ic, a solvent distillation
step and/or a solvent swap step is needed to improve reaction efficiency, either of
which increases free acid degradation. Additionally, the process of Scheme I utilizes
the formation of α-methylbenzylamine salts to provide the intermediate Ic in sufficiently
pure form that it can be used in the subsequent process step, however, the L-α-methylbenzylamine
counterion has been found to react with the isolation solvent, for example, isopropylacetate,
to form an N-acetyl-α-methylbenzylamine impurity. Furthermore, the L-α-methylbenzylamine
counterion has been found to compete with the amines of Formulae
Id and
Id' in the subsequent coupling reaction, and to form undesirable byproducts under the
reaction conditions of interest. Thus, when the salt intermediate is converted to
the free acid, the amine must be separated from the free acid prior to carrying out
the second coupling reaction when such processing schemes are employed.
[0009] What is needed is a process for providing the compound of Formula I which minimizes
the use of HOBT and which obviates the need to regenerate the free acid form of intermediate
compound Ic to carry out the second coupling step (Step 2) illustrated in Scheme I.
Summary of the Invention
[0010] Disclosed is a process for the provision of a compound of Formula I
said process comprising: (i) coupling a tertiaryamine salt of the compound of Formula
Ic
with a salt compound of Formulae Id or Id',
in the presence of at least one coupling reagent and at least one added moiety bearing
a basic nitrogen atom selected from a tertiary amine, a tertiary amide, a morpholine
compound, and mixtures of two or more thereof; and (ii) when the compound of Formula
Id selected in Step (i) is a compound of Formula
Id', oxidizing the compound produced in coupling Step (i) to yield the compound of Formula
I.
[0011] In some embodiments it is preferred to use a non-protic, polar organic solvent in
which to carry out the coupling reaction. In some embodiments of the invention it
is preferred to prepare run the coupling reaction with a coupling reagent in a medium
selected from ethyl acetate, N-methyl-2-pyrrolidinone (NMP), dimethyl formamide (DMF)
and mixtures of two or more thereof, more preferably the coupling reaction solvent
is ethylacetate in combination with a solvent selected from dimethylformamide (DMF)
and N-methyl-2-pyrrolidinone (NMP). In some embodiments it is preferred to use dimethylcylcohexylamine
as the counterion in the tertiary amine salt of the compound of Formula
Ic, thereby providing a compound of Formula
Ic'.
[0012] In some embodiments of the invention it is preferred to carry out the reaction using
a peptide coupling reagent comprising at least one moiety selected from ethyl(3-dimethylaminopropyl)-carbodiimide-HCl
(EDCI-HCl), carbonyldiimidazole (CDI), and 1-chloro-3,5-dimethoxytriazine (DMT-Cl),
optionally in conjunction with one or more reagents selected from 1-hydroxybenzotriazole
(HOBt), dimethylaminopyridine (DMAP), and 2-hydroxypyridine.
[0013] In some embodiments of the invention it is preferred to carry out the coupling reaction
in the presence of an added tertiary amine, more preferably a tertiary amine selected
from diisopropylethylamine (DIPEA), triethylamine (TEA), 2,6-lutidine, N-methylmorpholine
(NMM) and tetraethylenediamine.
[0014] In some embodiments of the invention it is preferred to use a coupling reagent selected
from coupling reagents comprising: (i) HOBt-monohydrate in combination with EDCI-HCl;
(ii) water wet HOBt in N-methylpyrrolidinone in combination with EDCI-HCl; (iii) DMAP
in combination with EDCI-HCl; (iv) carbonyldiimidazole (CDI) in DMF; (v) 1-chloro-3,5-dimethoxy-triazine;
(vi) triazine, for example, but not limited to, 1,3,5 trimethoxy-2,4,6-triazine and
2-hydroxypyridine in combination with EDCI-HCl. In some embodiments it is preferred
to add a tertirary amine selected from N-methylmorpholine and diisopropylethylamine.
[0015] In one aspect of the invention the process of the invention comprises a method of
forming the compound of Formula Ic, the method comprising:
- (a) treating a compound of Formula Ia
with a compound of Formula Ib
in the presence of EDCI-HCl and 2,6-lutidine and a non-polar, aprotic solvent suitable
to provide conditions to form the coupled amide-ester product of Formula Ica, for example, but not limited to, dimethyl formamide (DMF), N-methyl-2-pyrrolidone
(NMP), acetonitrile (ACN) or in a mixed solvent comprising acetonitrile and MTBE or
EtOAC;
- (b) working up the reaction product by sequential treatment with aqueous LiOH followed
by HCl and isopropyl acetate to liberate the free acid from the lithium carboxylate
form of the product; and
- (c) treating the free acid with a tertiary amine in a solvent selected from isopropyl
acetate, heptanes, heptane, and mixtures of two or more thereof, to precipitate the
tertiary amine salt of Formula Ic.
[0016] In some embodiments it is preferred to use acetonitrile as the solvent for step "a".
In some embodiments it is preferred to use N,N-dimethyl-N-cyclohexylamine as the tertiary
amine in Step "c".
[0017] In some embodiments it is preferred to use a form of the compound of Formula
Ib that comprises the (1 R, 2S, 5S) enantiomer in at least about 90% ee, more preferably
comprises the (1R, 2S, 5S) enantiomer in at least about 95% ee, more preferably comprises
the (1 R, 2S, 5S) enantiomer in at least about 98% ee., which ee is retained in the
coupling reaction to provide a compound of Formula
Ic reflecting the same diastereomeric excess. In some embodiments it is preferred to
use a form of the compound of Formula
Ib wherein at least about 90% of the amount of the compound of Formula
Ib comprises a mixture of two enantiomers, the (1R, 2S, 5S) enantiomer and the (1S,
2R, 5R) enantiomer, which composition of isomers is retained in the process of preparing
the compound of Formula
1c. In some embodiments it is preferred to employ a mixture in which at least about 95%
of the amount of the compound of Formula
Ib provided comprises a mixture of the (1S, 2R, 5R) enantiomer and the (1 R, 2S, 5S)
enantiomer in the process for the formation of the compound of Formula
1c, more preferably at least about 99% of the amount of the compound of Formula
Ib provided comprises a mixture of the (1R, 2S, 5S) enantiomer and the (1S, 2R, 5R)
enantiomer in the process for formation of the compound of Formula
1c.
[0018] Another aspect of the present invention is the provision of the compound of Formula
1c'.
Detailed Description
[0019] As used above, and throughout the specification, the following terms, unless otherwise
indicated, shall be understood to have the following meanings:
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and
comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain
about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower
alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
"Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which
may be straight or branched. The term "substituted alkyl" means that the alkyl group
may be substituted by one or more substituents which may be the same or different,
each substituent being independently selected from the group consisting of halo, alkyl,
aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl),
-N(alkyl)2, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include
methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl,
fluoromethyl, trifluoromethyl and cyclopropylmethyl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about
3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred
cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally
substituted with one or more "ring system substituents" which may be the same or different,
and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls
include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting
examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl
and the like.
"Heterocycl" means a cyclic ring system which contains one or more N, S, or O atoms
as a member of the ring structure in combination with up to 10 carbon atoms.
[0020] The following abbreviations are used in the description and examples below: RT (room
temperature); TEA (triethylamine); CDI (carbonyldiimidazole); DIPEA (diisopropylethylamine);
DMAP (N,N-dimethylaminopyridine); DMF (dimethyl-formamide); DMT-Cl (1-chloro-3,5-dimethoxytriazine),
EDCI (ethyl[(3-dimethylamino)propyl]carbodiimide): EtOAc (ethyl acetate); HOBt (1-hydroxy-benzotriazole);
IPA (isopropyl alcohol); NMM (N-methylmorpholine); NMP (N-methyl-2-pyrrolidinone);
Ac (acetyl); Et (ethyl); THF (tetrahydrofuran); eq (equivalent(s)); MTBE (tert-butylmethylether);
Boc (t-butoxy carbonyl).
[0021] As mentioned above, the compounds of Formula I have useful activity as HCV protease
inhibitors. The inventors have surprisingly found that compounds of Formula I can
be prepared in accordance with Scheme II, below, wherein the "R" groups of the amine
used in Step Ic are selected from alkyl, substituted alkyl, cycloalkyl and alkylcycloalkyl,
and substituted cycloalkyl moieties of from 1 to about 20 carbon atoms.
[0022] With reference to Scheme II, surprisingly, in comparison to previous processes, facile,
high yield amidation coupling occurs in Step 1 of the process of the invention, coupling
2-tertiarybutyl-ureido-3,3-dimethyl-butyric acid (the compound of Formula
(Ia)) to the azabicyclo compound of Formula
(Ib), in an amidation carried out without using 1-hydroxybenzo-triazole (HOBt) to mediate
the coupling reaction. Moreover, by carrying out Step 1 in acetonitrile (ACN) or in
a mixed solvent comprising acetonitrile and MTBE or EtOAC. Preferably ACN is used
in an amount of from about 3X to about 8X V/w relative to the starting material. Step
1 of Scheme II utilizes a tertiary amine to precipitate a salt form of the compound
of Formula (Ic), that can be employed directly in the subsequent coupling step without
first regenerating the free acid and removing the counter ion moiety used to prepare
the salt, as is necessary in previous processes, for example, those processes using
L-α-methylbenzylamine. This results in a more efficient process and better utilization
of later stage intermediate reagents in the multi-step preparation of compounds of
Formula I.
[0023] As will be appreciated, the compound of Formula Ib can have four stereoisomers, the
(1S, 2R, 5R) stereoisomer (shown in Scheme III as compound
Ib-L), the (1R, 2R, 5S) stereoisomer (not shown), the (1S, 2S, 5R) stereoisomer (not
shown) and the (1R, 2S, 5S) stereoisomer (shown in Scheme III as compound
Ib-D). In some embodiments it is preferred to use in Step I the compound of Formula
Ib in a form in which more than 90%, for example more than 98%, of the amount of the
isomers present comprise a mixture of the (1S, 2R, 5R) stereoisomer and the (1R, 2S,
5S) stereoisomer, wherein the two enantiomers are present in equal amounts. In some
embodiments it is preferred to use in step I the compound of Formula
Ib in a form in which one stereoisomer, the (1 R, 2S, 5S) isomer (Formula
Ib-D), is present in high enantiomeric excess, for example greater than about 90% ee, preferably
at least about 95% ee, more preferably at least about 98% ee. Enantiomeric excess
("e.e.") is a percentage expressing the extent to which one enantiomer (e.g., R-enantiomer)
is present over the others (e.g. S-enantiomer), calculated by subtracting the difference
in the amount of each enantiomer present divided by the sum of the amount of each
enantiomer present. Using a form of the compound of Formula
Ib that is selected for the desired mixture of enantiomers permits control of the relative
amount of the isomers present in the coupled product from the reaction.
[0024] The above-mentioned
U.S. Patent no. 7,012,066, and
U.S. patent application publication nos. 2005/0249702, published November 10, 2005,
2005/0059800, published March 17, 2005,
2005/0059648 published March 17, 2005 along with a copending application based on and claiming the priority of
U.S. provisional patent application Serial No. 60/753,215 filed December 22, 2005, describe how to provide the compound of Formula
Ib in a form containing the desired mixture of isomers or enrichment in one particular
isomer.
[0025] Step II of the inventive process, the second coupling step, carries out coupling
of the intermediate quarternary amine salt product produced in Step I of the inventive
process, for example, the compound of Formula
Ic, with, for example, the compounds of Fomulae
Id and
Id', preferably the compound of Formula
Id', The inventors have found that the use of mixed ethyl acetate and DMF or ethylacetate
and NMP as a solvent system in which the coupling is carried out, and the selection
of a tertiary amine as the counter ion in the salt form of the reagent in this second
step permits the present invention process to utilize the salt compound directly in
the reaction rather than needing to first regenerate the free acid form of product
(Ic), as was required in the prior processes mentioned above. Step 2 of the process of
the present invention is carried out in the presence of at least one additional moiety
- bearing a basic nitrogen atom and at least one peptide coupling reagent. Selected
conditions of the inventive process provide reduced impurities in the product of Formula
I.
[0026] Although it is advantageous to use both Steps I and II of the present process together,
it will be appreciated that some of the advantages offered by each of the individual
steps can be realized when practiced individually and integrated into published methods.
Each of these processing steps is discussed next in greater detail.
Step I - First Amidation Coupling Reaction.
[0027] The first step involves coupling the azabicyclo compound of Formula
(Ib) with the acid compound of Formula
(Ia). The coupling reaction is carried out in the presence of one or more 2,6-substituted
pyridine compounds, for example, 2,6-lutidine, and a coupling reagent, for example,
the hydrochloride salt of (ethyl[(3-dimethylamino)propyl]carbodiimide) (Formula
Ia1).
Suitable solvents for carrying out the reaction are polar, aprotic, organic solvents,
for example, acetonitrile and ethyl acetate (EtOAC). Preferably the reaction is carried
out at a temperature of from about 5 °C to about 30°C. In general, the reaction is
run using one equivalent of the compound of formula
Ia and an amount of the compound of Formula
Ib which is from about 0.9 equivalents to about 1.1 equivalents in comparison to the
amount of the compound of Formula Ia employed. In general, the reaction will use one
or more pyridine base in an amount of from about 0.5 eq. to about 2.5 eq. relative
to the amount of the compound of Formula Ia employed, and one or more coupling agents
in an amount of at least 1.05 equivalents relative to the amount of the compound of
Formula Ia employed. In general, the reaction will be run for four hours to insure
complete coupling of the starting materials. Typically the reaction will be followed
by LC and considered completed when less than about 0.75 % of the starting compound
of Formula Ia remains in the reaction mixture.
[0028] Although it is preferred to employ EDCI as a coupling agent in the reaction, other
coupling agents may be used instead of EDCI or in addition to EDCI, for example pivaloyl
chloride, propane phosphonic acid anhydride and mixed (EDCI/DMAP). It is preferred
to employ 2,6-lutidiene as a substituted pyridine base, but it will be appreciated
that other pyridine bases, for example, other 2,6 alkyl-sustituted pyridines, triethyl
amine, and NMM can also be employed instead of 2,6-lutidine or in addition to 2,6-lutidine.
[0029] After the coupling reaction has run to completion, the reaction mixture is worked
up by adding methyl tert-butyl ether to the reaction mixture, and washing the resultant
mixture with HCl aqueous solution followed by sodium bicarbonate solution, then concentrating
the organic layer to 3X (that is, to about 1/3 of its initial volume), which, after
concentration, contains primarily acetonitrile. The reaction mixture is subsequently
treated with a metal hydroxide base in water, followed by HCl or another suitable
acid, for example, H
2SO
4, followed by a solvent selected from isopropyl acetate and 2-methyltetrahydrofuran
(Me-THF), thereby liberating the free acid form of the product of Formula
Ic.
[0030] After liberation of the free acid form of the compound of Formula Ic, the reaction
mixture is treated with a tertiary amine to precipitate an ammonium salt form of the
compound of Formula
Ic. As shown in Scheme II, the tertiary amine interacts with the free acid functionality
of the compound forming a counter ion in the salt. In some embodiments it is preferred
to use a single component solvent, preferably isopropyl acetate. In some embodiments
it is preferred to include an antisolvent mixed with the solvent in which the tertiary
amine is dissolved, for example, isopropyl acetate/heptanes. In these embodiments,
mixture of the reaction mixture with the tertiary amine solution results in precipitation
of a salt form of a compound of Formula
1c, which can be collected by filtration and dried for use in Step 2. In some embodiments
it is preferred to use N,N-dimethyl-N-cyclohexyl amine as the tertiary amine for precipitating
the coupled product.
Step II - Second Amidation Coupling Redaction.
[0031] The second step of the process of the invention for preparing the compound of Formula
I is to carry out a second coupling reaction between the ammonium salt compound
Ic provided by the Step I and a salt compound selected from the compound of Formula
Id and the compound of Formula
Id'. In some embodiments of the invention it is preferable to utilize the compound of
Formula Id'. Accordingly, the second amidation coupling reaction is carried out by
reacting the compound of Formula
Ic with the selected salt compound of Formula
Id in the presence of at least one peptide coupling reagent and one or more reagents
containing a basic nitrogen atom selected from a tertiary amine, an amide, and a morpholine
compound and mixtures of two or more thereof. Generally the reaction is carried out
at a temperature of from about -10 °C to about +30°C, preferably less than about 30°C.
[0032] In some embodiments it is preferred to use ethyl acetate as the solvent. Other solvents
which may be used include dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dimethylacetamide,
and acetonitrile (ACN), and mixtures of two or more thereof. Suitable peptide coupling
reagents for use in the present invention process Step II include, but are not limited
to, for example, 1-hydroxy-benzotriazole (HOBt, both water wet and hydrate), ethyl[(3-dimethylamino)propyl]carbodiimide-hydrochloride
(EDCI-HCl); carbonyldiimidazole (CDI), 1-chloro-3,5-dimethoxytriazine (DMT-Cl), 2-hydroxypyridine,
and combinations of two or more thereof. In some embodiments of the present invention
it is preferred to utilize the selected coupling agent(s) in a solvent selected from
ethyl acetate, dimethyl formamide (DMF), N-methyl-2-pyrrolidone (NMP), and combinations
of two or more thereof. In some embodiments of the present invention it is preferred
to utilize one or more moieties containing a basic nitrogen atom selected from triethylamine,
diisopropylethylamine, 2,6,-lutidine, N-methylmorpholine, and tetramethylethylene
diamine.
[0033] In some embodiments of the invention it is preferred to use a coupling reagent comprising
one or more coupling agents and a solvent selected from the following combinations:
(i) HOBt-monohydrate in ethyl acetate with DMF or NMP in combination with EDCI-HCl;
(ii) water wet HOBt in ethylacetate with N-methylpyrrolidinone in combination with
EDCI-HCl; (iii) DMAP in ethylacetate with DMF or N-methyl pyrrolidinone (NMP) in combination
with EDCI-HCl; (iv) carbonyldiimidazole (CDI) in ethylacetate and DMF; (v) 1-chloro-3,5-dimethoxy-triazine
in ethylacetate with DMF; (vi) 1,3,5 trimethoxy-2,4,6-triazine; and (vii) 2-hydroxypyridine
in ethyl acetate with DMF with EDCI-HCl. In some embodiments it is preferred to add
the tertiary amine diisopropylethylamine or N-methyl morpholine as a moiety having
a basic nitrogen atom.
[0034] In general the ratio of the amount of ammonium salt of Formula
Ic to the amount of salt compound of Formula
Id used with be from about 0.76 equivalents of ammonium salt
Ic: 1.0 equivalent of the salt compound of Formula
Id to about 1.0 equivalent ammonium salt
Ic: 1.1 equivalent salt compound of Formula
Id, preferably a ratio of 1:1.1 will be employed. In general, the amount of coupling
agent used will be at least about 1.05 equivalents, based on the amount of ammonium
salt of Formula
Ic employed. In general the amount of added tertiary amine provided with be from about
0.5 equivalents to about 2.5 equivalents, preferably from about 0.75 equivalents to
about 2.0 equivalents based on the amount of the compound of Formula
Ic present.
[0035] In those embodiments in which the salt compound of Formula
Id' was employed, with reference to Scheme I, above, a second step (2'b) is carried
out in which the -OH functional group of the adduct is oxidized to provide the corresponding
ketone, thus providing the compound of Formula
I. This oxidation can be carried out in accordance with procedures in the above-mentioned
patents and published applications, for example, the procedure described in
U.S. patent application no. 7,012,066 at column 451, lines 20 to 29, and the procedure described in copending U.S. application
filed November 13, 2006 under attorney docket no. CD06366L01.
[0036] The starting materials used in Step I of the present process, and the salt compounds
of Formula
Id used in Step II of the present process can be prepared in accordance with procedures
described in any of the above-mentioned patents and published applications.
EXAMPLES
Example I - Preparation of Ic' (N,N-dimethylcyclohexyl amine salt) according to Scheme II, Step) I.
[0037] Into a reactor (R-1) was charged 351 kg of compound
Ia, 314 kg of compound
Ib, and 807 L of acetonitrile. Batch temperature was adjusted to 0 to 10 °C. 323kg of
2,6-lutidine followed by 123 L of acetonitrile was charged to R-1, while maintaining
temperature at 0 to 15 °C. 351 kg of EDCI-HCl followed by 123 L of acetonitrile was
charged to between 5 to 25 °C. The mixture was stirred at 20 to 30 °C for 4 h. Reaction
completion was checked by HPLC to show less than 0.75% of un-reacted compound
Ia. 1755L of MTBE followed by 807 kg of 9.9% HCl was charged to R-1 between 15°C to
25 °C. The batch was stirred for 15 minutes and settled for at least 30 minutes, and
the aqueous layer was split to HOLD TANK. 807 kg of 9.9% HCl was charged to R-1 at
15 to 25 °C. The batch was stirred for 15 minutes and settled for 30 minutes, and
the aqueous layer was split to HOLD TANK. 211 kg of sodium bicarbonate followed by
4001 L of water was charged to R-2, and the whole was agitated until all solid dissolved.
1404 L of the NaHCO
3 solution in R-2 was transferred to R-1 at 15 to 25 °C. The mixture was stirred for
15 minutes and settled for at least 30 minutes. The aqueous layer was split to HOLD
TANK. 140 kg of sodium chloride was charged to the NaHCO
3 solution in R-2. Half of the NaHCO
3/ NaCl solution in R-2 was transferred to R-1. The whole in R-1 was agitated for 15
minutes and settles for at lest 30 minutes. The aqueous layer was split to HOLD TANK.
The remainder of the NaHCO
3/ NaCl solution in R-2 was transferred to R-1. The whole in R-1 was agitated for 15
minutes and settled for at lest 30 minutes. The aqueous layer was split to HOLD TANK.
The batch in R-1 was concentrated to about 1053 L under vacuum. 97 kg of lithium hydroxide
Monohydrate followed by 1404 L of water was charged to R-2, and the mixture was stirred
at 20 to 30 °C until all solids dissolved. The lithium hydroxide solution in R-2 was
transferred to R-1. The whole was stirred at 20 to 30 °C for 3h. Hydrolysis completion
was checked by HPLC to show 100% conversion. 1053 L of MTBE followed by 1404 L of
water was charged to R-1. The mixture was stirred for 20 minutes and settles for at
least 30 minutes. The aqueous layer was split to R-2. The organic layer was transferred
to HOLD TANK. 1053 L of MTBE was charged to R-2. The mixture was stirred for about
10 minutes and settled for at least 30 minutes. The aqueous layer was transferred
to R-1. The organic layer was transferred to HOLD TANK. 293 kg of 9.9% HCl followed
by 1530 kg of isopropyl acetate and 660 kg of 9.9 % HCl was charged to R-1 at 20 to
30 °C. The mixture in R-1 was stirred for 30 minutes and settled for at least 30 minutes.
The aqueous layer was split to HOLD TANK. 35 kg of Sodium Chloride followed by 702
L of water was charged to R-2. The NaCl solution in R-2 was transferred to R-1. The
mixture was stirred for 15 minutes at 15 to 25 °C and settled for at least 30 minutes.
The aqueous layer was split to HOLD TANK. The batch in R-1 followed by 306 kg of isopropyl
acetate rinse was transferred to R-2 via 1 µm inline filter. The batch in R-2 was
concentrated to about 1404 L under vacuum at 35 to 60 °C. 918 kg of isopropyl acetate
was charged to to R-2, and the batch was concentrated to about 1404 L under vacuum
at 35 to 60 °C. Water content in the batch was <0.5% w/w. 1530 kg of isopropyl acetate
was charged to R-2. The batch temperature was adjusted to 43 to 48 °C, and 109 kg
of N,N-dimethylcyclohexylamine (DMCA) was charged to R-2. 4 kg of compound
Ic' seed in 11 L of isopropyl acetate was charged to R-2. The batch was stirred for 5
h at 43 to 48 °C for 1 h. 130 kg of DMCA was charged to R-2 over 2 h at 43 to 48 °C.
153 kg of isopropyl acetate rinse was charged to R-2. The batch was cooled to 5 to
10 °C over a period of 3 hours. The batch was filtered in portions with a centrifuge.
The wet cake was washed with cold isopropyl acetate and was dried under vacuum at
25 °C for 4 h followed by at 45 °C for at least 8 h. 706 kg of Compound
Ic' was obtained (90% yield).
1H NMR (DMSO-d
6), δ 0.80 (s, 3H), 0.91 (s, 9H), 0.99 (s, 3H), 1.02-1.25 (m, 5H), 1.17 (s, 9H), 1.35
(d,
J = 8 Hz, 1H), 1.43 (dd,
J = 5 and 8 Hz, 1H), 1.54-1.58 (m, 1H), 1.68-1.78 (m, 3H), 2.23 (s, 6H), 2.28 (m, 1H),
3.73 (dd,
J = 5 and 10 Hz, 1 H), 3.96 (d,
J = 10 Hz, 1H), 4.08 (s, 1H), 4.15 (d,
J = 10 Hz, 1H), 5.87 (d,
J = 10 Hz, 1 H), 5.95 (brs, 1 H).
Example 2 - Preparation of the compound of Formula Ix According to Scheme II, Step 2 using
wet HOBT in NMP with EDCI-HCl Present.
[0038] Into a reactor was charged 80 mL of ethylacetate to a reactor followed by 20.01 g
(40.4 mmol) of
Ic', and 9.20 g (44.1 mmol, 1.09 equivalents) of
Id'. An additional 20 mL of ethyl acetate and 20.5 g N-methylpyrrolidinone was charged
into the reactor. The reactor contents were cooled to 15 °C. Additionally 3.67 g (27.16
mmol, 0.59 equivalents) of 1-hydroxybenzotriazole monohydrate followed by 2.96 g of
water were charged. N-methylmorpholine (2.83 g, 28.0 mmol, 0.63 equivalents) and subsequently
ethyl[(3-dimethylamino)propyl]carbodiimide-hydrochloride (EDCI-HCl), (9.98 g, 52.1
mmol, 1.30 equivalents) were sequentially charged into the reaction mixture. The reaction
mixture was stirred at 15 °C until complete (< 0.5 area %
Ic' remaining by LC analysis), in this case 3h.
[0039] The reactor temperature was increased to 20 °C and 80 mL of DI water followed by
40 mL of 9.9% aqueous hydrochloric acid was added. The reactor was stirred at 20 °C
for 13 minutes then allow to split for 90 minutes. The aqueous layer was removed and
treated with 60 mL of ethyl acetate. This mixture was stirred at 20 °C for 20 min
then allowed to split for 25 minutes. The organic layer was combined with the previous
organic layer. The combined organic layers were treated with 80 mL DI water and 40
mL 9.9 % aqueous hydrochloric acid. The mixture was stirred at 20 °C for 15 minutes
then allowed to split for 28 minutes. The aqueous layer was removed to waste. The
organic layer was treated with 120 mL of 0.45M potassium carbonate solution and stirred
at 20 °C for 21 minutes then allowed to split for 30 minutes. This aqueous layer was
removed to waste. The organic layer was then treated with 120 mL of 0.45M potassium
carbonate solution and stirred at 20 °C for 31 minutes then allowed to split for 28
minutes with subsequent removal of the aqueous layer to waste. The organic layer was
treated with 120 mL of DI water and stirred at 20 ºC for 15 minutes then the layers
were allowed to split for 59 minutes. The aqueous layer was removed to waste. Solution
yield by LC of the compound of Formula
Ix in organic layer is 92%.
Example 2a
[0040] On a similar batch with 100g starting
Ic' the organic layer obtained containing the compound of Formula
Ix was then concentrated to 486.45 g. 162.17 g of this material (KF= 5.6 %) was treated
with 92 mL of ethyl acetate and concentrated by rotary evaporation to 98 mL then treated
with 7 mL ethyl acetate (KF= 3.0 %). 0.75 mL of DI water was added to bring the KF
to 3.8%. This ethyl acetate solution was added slowly by syringe pump over 2h to -10
ºC heptanes in a round bottom flask. Following the addition, the slurry was stirred
at -10 ºC for 15 minutes then filtered and washed with 66 mL then 55 mL of cold heptanes.
The white solid was dried on the filter for 30 minutes then in a room temperature
vacuum oven for 3 days. The temperature on the vacuum oven was increased to 70 ºC
for 1 day. The final solid amount of the compound of Formula was 31.51 g, 89.6 % yield.
Example 3 - Preparation of the compound of Formula Ix According to Scheme II, Step 2 using
HOBT Monohydrate with EDCI-HCl Present.
[0041] EDCI-HCl (244.00 kg, 1272 mol, 1.27 equiv), 1-hydroxybenzotriazole hydrate(80.00
kg, 592 mol, 0.59 equiv), and 236.00 kg (1131 mol, 1.13 equiv) of the compound of
Formula
1d' (Scheme II, Step 2) were charged to a reactor and dissolved in DMF (1407 kg) and
ethyl acetate (1492 L). The reaction was cooled to 6.2 ºC and diisopropylethylamine
(80.00 kg, 619 mol, 0.62 equiv) was added followed by 525.00 kg of the compound of
Formula Id' (94.68 % w/w, 1004 mol, 1.00 equiv) as a solid charge. The reaction mixture
was maintained at a temperature of from 0 °C to 10 ºC, with stirring, for 30 min then
warmed to 20 °C to 25 ºC over 1.5 hour and maintained, at a temperature of 20 °C to
25 ºC for 3.5h with continued stirring. The reaction temperature was adjusted to 15
°C to 25 ºC and water (2486.5 L) and ethyl acetate (3486.8 L) were added followed
by 36% HCl (224.00 kg). This mixture was agitated for 15 minutes then the aqueous
layer was removed. The aqueous layer was back-extracted with ethyl acetate (5438 L).
The combined organics were treated with water (1988.5 L) and 36 % HCl (70.00 kg).
This mixture was agitated for 15 minutes and the aqueous layer was removed. The organic
layer was then treated with 0.45 M K
2CO
3 (aq) (1991.2 L water and 124.00 kg K
2CO
3). This mixture was agitated for 15 minutes and the aqueous layer was removed. The
organic layer was treated with 0.75 M KHCO
3 (aq) (2010 L). This mixture was agitated for 15 minutes and the aqueous layer was
removed. The organic layer was treated with 0.75 M KHCO
3 (aq) (1935 L). This mixture was agitated for 15 minutes and the aqueous layer was
removed. The organic layer was treated with water (1989.6 L). This mixture was agitated
for 15 minutes and the aqueous layer was removed. The organic layer was concentrated
under vacuum to 1590 L, water (19.1 L) was added, and the mixture was added to -10
ºC heptanes (7457.3 L) over 2.5 h. The resultant solid product was isolated by centrifuge
filtration, washed with cold heptanes, and dried under vacuum at 30 ºC for 6h then
70 ºC for 15h to give the compound of Formula
Ix as a white solid (473.55 kg, 90.4 %).
Example 4 - Preparation of the Compound of Formula Ix According to Scheme II, Step 2 Using HOBT with EDCI-HCl Present and Selected Enantiomers
of the Compound of Formula 1d'.
[0042] The compound of Formula
1d' (Scheme II, Step 2) comprising 2.5 g (12 mMol.) of the combined (S,S and R,R) enantiomers
and 0.25 g (1.2 mMol.) of the combined (R,S and S,R) enantiomers (enantiomeric pair
ratio 87/13, [(RR+SS)/(RS+SR)]) were combined with 1.0 g of 1-hydroxybenzotriazole
hydrate (HOBT, 7.4 mmol) in 21 ml of ethyl acetate. This mixture was cooled to a temperature
between 0 °C to 5°C. To the reaction mixture was added 2.1 g of N, N-diisopropylethylamine
(16.2 mmol), 5 ml of 1-methyl-2-pyrrolidinone, and 4.7 g of the compound of Formula
1 c' (9.5 mmol), followed by 2.85g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI HCl, 14.9 mmol). The temperature of the reaction mixture was maintained
between 0 °C and 10°C with stirring for 15 min, then slowly warmed to a temperature
between 20 °C and 25°C and maintained in that temperature range with stirring overnight.
At the end of the stirring period, 40 mL of ethyl acetate and 25 mL of 3N of HCl where
added to the reaction mixture while maintaining the temperature between 15 °C and
25 °C. The layers were separated. The organic layer was washed successively with one
aliquot of 15 ml of 3N of HCl, one aliquot of 15 ml of water, three aliquots of 20
mL of 10% of potassium carbonate in water, and one 20 mL aliquot of water. The organic
layer was concentrated, added ethyl acetate again, and concentrated to dry. The product
of Formula
Ix was obtained as a white powder (3.3 g, in a ratio of 87/13 of (RR+SS)/(RS+SR).
Example 5 - Preparation of the Compound of Formula Ix According to Scheme II, Step 2 Using HOBT with EDCI-HCl Present and Selected Enantiomers
of the Compound of Formula 1 d'.
[0043] The compound of Formula
1d' (Scheme II, Step 2) comprising 2.5 g (12 mMol.) of the combined (S,R and R,S) enantiomers
and 0.25 g (1.2 mMol.) of the combined (S,S and R,R) enantiomers (enantiomeric pair
ratio 10/90, [(RR+SS)/(RS+SR)]) were combined with 1.0 g of 1-hydroxybenzotriazole
hydrate (HOBT, 7.4 mmol) in 21ml of ethyl acetate. This mixture was cooled to a temperature
between 0 °C to 5°C. To the reaction mixture was added 1.8 g of N, N-diisopropylethylamine
(13.9 mmol), 5 ml of 1-methyl-2-pyrrolidinone, and 4.7 g of the compound of Formula
1c' (9.5 mmol), followed by 2.35g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI HCl, 12.2 mmol). The temperature of the reaction mixture was maintained
between 0 °C and 10°C with stirring for 15 min, then slowly warmed to a temperature
between 20 °C and 25°C and maintained in that temperature range with stirring overnight.
At the end of the stirring period, 40 mL of ethyl acetate and 25 mL of 3N of HCl where
added to the reaction mixture while maintaining the temperature between 15 °C and
25 °C. The layers were separated. The organic layer was washed successively with one
aliquot of 15 ml of 3N of HCl, one aliquot of 15 ml of water, one aliquot of 20 mL
of 10% of potassium carbonate in water, and one 20 mL aliquot of water. The organic
layer was concentrated, added ethyl acetate again, and concentrated to dry. The product
of Formula
Ix was obtained as a white powder (3.8 g, in a ratio of 10/90 of (RR+SS)/(RS+SR).
Example 6 - Preparation of the Compound of Formula Ix via Intermediate Prepared From CDI Treatment of the Compound of Formula Ic'.
[0044]
[0045] The compound of Formula Ix was produced in coupling reactions using CDI in accordance
with the following procedure:
- 1. Charge 53.2g 1C' salt (94.3 wt/wt%, 50g active)
- 2. Charge 150 ml (3X) DMF (KF: 0.1 %);
- 3. Charge 11-16ml DIPEA (0.8 -1.2 eq., KF: 0.04%) and then 19.2g (1.15 eq.) CDI;
- 4. Agitate batch at rt for 2-3 hr
Note: add more CDI to push reaction to completion if needed;
- 5. charge 23.75g (1.12 eq.) 1d' at ambient temperature, agitate at ambient temperature until reaction is completed;
- 6. cool batch to 10°C and add 350 ml (7X) EtOAc and then 250 ml (5X) water;
- 7. adjust pH of the aqueous layer to -0.5 with concentrated HCl maintaining reaction
mixture at 15 °C -20 °C and split layers;
- 8. wash organic layer with 1 N HCl 2-3 times;
- 9. wash organic layer with two aliquots of 8-10% aqueous K2CO3 and/or KHCO3 solution;
- 10. wash organic layer with 4X water
- 11. assay and/or isolate from organic layer, typically 80.3% solution yield of the
compound of Formula Ix with 98.95 area % purity
Example 7a - Preparation of the Compound of Formula Ix According to Scheme II Using 2-Hydroxypyridine As a Coupling Agent in the Presence
of EDCI-HCl
[0046] Into a reaction vessel containing 100 mL of a 1:1 mixture of methyl t-butyl ether
and DMF at room temperature were suspended 11.70 g of EDCI-HCl (61.0 mmol, 1.62 equiv),
11.31 g of the compound of Formula
Id' (54.2 mmol, 1.44 equiv), and 2.64 g of 2-Hydroxypyridine (27.8 mmol, 0.74 equiv).
Diisopropylethylamine (12.8 mL, 73.5 mmol, 1.95 equiv) was added to the reaction mixture
followed by a 20.00 g charge of the compound of Formula
Ic' in solid form ((93.1% w/w), 37.6 mmol, 1.00 equiv). The reaction mixture was stirred
over night at room temperature (19 °C to 22 ºC) and monitored by HPLC for completion.
At the end of the stirring period, 50 mL of methyl t-butyl ether and 50 mL of 2.5
% aqueous HCl were added to the reaction mixture. The aqueous layer was back-extracted
with 4 aliquots of 50 mL methyl t-butyl ether. The combined organic layers were washed
sequentially with 100 mL 2.5 % HCl (aq), 100 mL 1 % HCl (aq), 100 mL water, 100 mL
0.45 M K
2CO
3 (aq), 100 mL 0.75 M KHCO
3 (aq), and 100 mL water. The organic layer was concentrated to 136 mL and cooled to
10 °C. To the cold, concentrated organic layer was added 200 mL 0 ºC heptanes over
50 minutes. The resulting slurry was agitated for 50 minutes, and the solids were
isolated by filtration and washed with 35 mL heptanes. The solids thus obtained were
dried under vacuum at 75 ºC overnight to give ∼1 g white solid (loss to filtrate and
flask walls 4.59 g) of the desired product (total yield 26.6 %).
Example 7b- Preparation of the Compound of Formula Ix According to Scheme II Using DMAP As a Coupling Agent in the Presence of EDCI-HCl.
[0047] Into a reaction vessel containing 120 mL of a 1:1 mixture of ethyl acetate and DMF
at room temperature were suspended 9.75 g EDCI-HCl (50.9 mmol, 1.35 equiv), 9.79 g
of the compound of Formula
Id' (46.9 mmol, 1.24 equiv), and 2.76 g DMAP (22.6 mmol, 0.60 equiv). Diisopropylethylamine
(10.2 mL, 58.6 mmol, 1.51 equiv) was added to the reaction mixture followed by a 20.03
g charge of the compound of Formula
Ic' in solid form ((93.1% w/w), 37.7 mmol, 1.00 equiv). The reaction mixture was stirred
for 17 hours at room temperature (19 °C to 22 ºC) and monitored by HPLC for completion.
When the reaction was complete, 50 mL of ethyl acetate and 100 mL of 2.5 % aqueous
HCl were added to the reaction mixture. The aqueous layer was back-extracted with
60 mL ethyl acetate. The combined organic layers were washed sequentially with 80
mL 1 % HCl (aq), 80 mL water, 80 mL 0.45 M K
2CO
3 (aq), 80 mL 0.75 M KHCO
3 (aq), 80 mL 0.75 M KHCO
3 (aq), and 80 mL water and then concentrated by rotary evaporation to 47.45g. The
SS isomer crystallized from the concentrate and 2.75ml of water was added to the slurry.
The SS isomer dissolved within 4-5 hours. The organic concentrate was added to 171
mL of 0 ºC heptanes over 47.5 min. and stirred at 0ºC for 30 min. Solids precipitated
from the mixture and the solid product isolated by vacuum filtration. The solids thus
obtained were dried at 75 ºC in a vacuum oven for 18 h to provide 11.2 g (56.9 % yield,
91.0 % wt/wt purity) of the compound of Formula
Ix.
Example 7c- Preparation of the Compound of Formula Ix According to Scheme II Using 1,3,5-Trimethoxy-2,4,6 Triazine a Coupling Agent in
the Presence of EDCI-HCl.
[0048] Into a reaction vessel containing 100 mL of a 1:1 mixture of ethyl acetate and DMF
at room temperature were suspended 7.56 g of 1,3,5-trimethoxy-2,4,6-triazine (43.1
mmol, 1.13 equiv) and 9.79 g of the compound of Formula
Id' (46.9 mmol, 1.23 equiv). N-Methylmorpholine (4.7 mL, 42.7 mmol, 1.12 equiv) was added
to the reaction mixture followed by a 20.01 g charge of the compound of Formula
Ic' in solid form ((93.9% w/w), 38.0 mmol, 1.00 equiv). The reaction was stirred for
25.5 hours at room temperature (19 °C to 22 ºC) and monitored by HPLC for completion.
When the reaction was complete to the reaction mixture was added 50 mL of ethyl acetate
and 100 mL of 1M aqueous citric acid. The aqueous layer was back-extracted with 60
mL ethyl acetate. The combined organic layers were washed sequentially with 100 mL
1 M citric acid (aq), 80 mL 1 M citric acid (aq), 85 mL water, 80 mL 0.45 M K
2CO
3 (aq), 80 mL 0.75 M KHCO
3 (aq), 80 mL water, and 80 mL 1 M citric acid (aq). HPLC analysis indicated that the
solution contained an 84.7 % yield of the Compound of Formula
Ix.
1. Ein Verfahren zur Bereitstellung einer Verbindung der Formel I
wobei das Verfahren umfasst:
(i) Verknüpfen einer Verbindung der Formel la
mit einer Verbindung der Formel Ib
in Anwesenheit von Ethyl[(3-dimethylamino)propyl]carbodiimid-Hydrochlorid (EDCI-HCl),
2,6-Lutidin und einem Lösungsmittel, das geeignet ist zur Bereitstellung von Bedingungen
zur Bildung einer Reaktionsmischung, welche das verknüpfte Amid-Produkt der Formel
Ica enthält
(ii) Aufarbeiten der in Schritt (i) erzeugten Reaktionsmischung durch nacheinanderfolgende
Behandlung der Reaktionsmischung mit LiOH in Wasser, gefolgt von HCl in Isopropylacetat,
um die die freie Säure aus der Acetat-Form des Produkts freizusetzen,
(iii) Behandeln der in Schritt (ii) erzeugten freien Säure mit einem tertiären Amin
in Isopropylacetat, um das tertiäre Aminsalz der Formel Ic auszufällen,
(iv) Verknüpfen des tertiären Aminsalzes der Formel Ic
mit einer Verbindung, ausgewählt aus den Salzverbindungen der Formeln Id und Id'
in Anwesenheit von wenigstens einem Peptid-Kupplungsreagenz und wenigstens einem Reagenz
mit einem basischen Stickstoffatom, ausgewählt aus einem tertiären Amin, einem tertiäre
Amid, einer Morpholin-Verbindung und Mischung aus zwei oder mehreren davon, und
(v) wenn die in Schritt (iv) ausgewählte Salzverbindung eine Verbindung der Formel
Id' ist, die Oxidation der in Schritt (iv) erzeugten Verbindung Ic, um die Verbindung
der Formel I zu erhalten.
2. Ein Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, dass Schritt (iv) in einem polaren organischen Lösungsmittel durchgeführt wird, das ausgewählt
ist aus Ethylacetat, Acetonitril, Dimethylformamid, Dimethylacetamid und N-Methyl-2-pyrrolidinon
(NMP) sowie Mischungen aus zwei oder mehreren davon.
3. Ein Verfahren gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass das Gegenion R3N in der Verbindung der Formel Ic N,N-Dimethylcyclohexylamin ist.
4. Ein Verfahren gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet dass das Peptidkupplungsreagenz ausgewählt ist aus: (i) HOBt-Monohydrat in Ethylacetat
mit Dimethylformamid (DMF) zusammen mit EDCI-HCl; (ii) HOBt-Monohydrat in Ethylacetat
mit NMP zusammen mit EDCI-HCl; (iii) feuchtes HOBt in Ethylacetat mit NMP zusammen
mit EDCI-HCl; (iv) DMAP in Ethylacetat mit NMP zusammen mit EDCI-HCl; (v) DMAP in
Ethylacetat mit DMF zusammen mit EDCI-HCl; (vi) Carbonyldiimidazol (CDI) in Ethylacetat
mit DMF; (vii) 1-Chlor-3,5-dimethoxytriazin in Ethylacetat mit DMF; (viii) 1,3,5-Trimethoxy-2,4,6-triazin
in Ethylacetat mit DMF; und (ix) 2-Hydroxypyridin in einer Ethylacetat/DMF-Mischung
in Gegenwart von EDCI-HCl.
5. Ein Verfahren gemäß Anspruch 4, dadurch gekennzeichnet, dass das Reagenz mit einem basischen Stickstoffatom, welches in Schritt (iv) zugegeben
wird, ausgewählt ist aus Diisopropylethylamin, N-Methylmorpholin, Triethylamin, 2,6-Lutidin
und Tetramethylethylendiamin.
6. Ein Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, dass das Lösungsmittel, welches in Schritt (i) ausgewählt wurde, Acetonitril ist.
7. Ein Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, dass das tertiäre Amin, welches in Schritt (iii) verwendet wird, N,N-Dimethyl-N-cyclohexylamin
ist.
8. Ein Verfahren gemäß Anspruch 7,
gekennzeichnet dadurch dass die Form der Verbindung der Formel Ib, welche im Verknüpfungsschritt (i) verwendet
wird, einen Enantiomerenüberschuss (ee) von wenigstens 90% ee des (S,R,S)-Enantiomers
der Formel (Ib-D) umfasst
9. Ein Verfahren gemäß Anspruch 8, dadurch gekennzeichnet, dass die Verbindung der Formel Ib wenigstens 95% ee des (S,R,S)-Enantiomers der Formel
(Ib-D) umfasst.
10. Ein Verfahren gemäß Anspruch 8, dadurch gekennzeichnet, dass die Verbindung der Formel Ib wenigstens 98% ee des (S,R,S)-Enantiomers der Formel
(Ib-D) umfasst.
11. Ein Verfahren gemäß Anspruch 8, dadurch gekennzeichnet, dass die Verbindung der Formel Ib wenigstens 99% ee des (S,R,S)-Enantiomers der Formel
(Ib-D) umfasst.
12. Eine Verbindung der Formel Ic'